J Gastroenterol 2005; 40:1163–1166 DOI 10.1007/s00535-005-1718-5

Editorial Is the new diagnostic scoring system of Zeniya and colleagues useful for autoimmune liver diseases? Article on page 1148 Diagnosing clinical subsets of autoimmune liver diseases based on a multivariable model Zeniya M, Watanabe F, Morizane T, et al.

Autoimmune liver diseases consist of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Although they share a presumed autoimmune pathogenesis; the clinical features, disease courses, and responses to therapy are quite distinct in typical patients with these three diseases. On the other hand, some patients show clinical, biochemical, and histological features reminiscent of both AIH and PBC. These features are known as called “overlap syndrome”, “mixed type chronic aggressive hepatitis (CAH) and PBC”, and “autoimmune cholangiopathy (AIC)”. However, these disease entities are controversial. AIH was established as an independent disease entity by Mackay et al.1 Persistent hepatocyte injury occurs by an immunogenic mechanism associated with an autoimmune antibody, such as antinuclear antibody (ANA), and high g-globulinemia. In liver biopsy specimens, multilobular necrosis, interface hepatitis, plasma cell infiltration, and hepatocyte rosette formation are observed. Typically, reddish markings and gutter-like depressions on the liver are observed by peritoneoscopy. A scoring system for the diagnosis of AIH to be used internationally was proposed by the International Autoimmune Hepatitis Group.2 Definite or probable AIH is diagnosed by calculating the total score. The scoring system was reassessed in 1999 to exclude druginduced hepatitis and biliary diseases.3 In Japan, after several consensus meetings, guidelines for the diagnosis and therapy of AIH were recommended.4,5 There are several specific types of AIH. Although the above scoring system provides insight about the diagnosis, attention should be given to many other factors. (1) Type II AIH is prominent in children and is diagnosed by the presence of liver kidney microsomal 1 antibody. Patients with type III AIH express antibody to soluble

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liver antigen. The incidence and prevalence of type II and type III AIH are almost nil in Japan. (2) AIH with features of acute hepatitis has been reported in 25% of patients with AIH in Europe,6 but, there are few patients with such features in Japan. However, if these features are found in middle-aged female patients, the diagnosis should be done cautiously. The diagnosis of AIH with features of acute hepatitis is sometimes difficult because of low ANA titers and low levels of IgG/g-globulin.7 However, the titers of ANA and the levels of IgG/g-globulin are elevated in the course of disease pathogenesis. In some AIH patients with features of acute hepatitis, fulminant hepatitis occurs. In addition, we have reported a patient with acute exacerbation of AIH showing spontaneous remission and acute exacerbation.8 (3) Latent AIH has been reported among patients with non-B, non-C chronic hepatitis in Japan.9 (4) There are pediactric patients with AIH.10 They mostly show features of acute hepatitis, a low ANA titer, and low levels of IgG. (5) Some patients with nonalcoholic steatohepatitis may express ANA in their sera. PBC was defined by the presence of antimitochondrial antibody (AMA) in sera and chronic nonsuppurative destructive cholangitis (CNSDC) in liver biopsy specimens. Typically, gentle undulations and reddish patches on the liver are observed by peritoneoscopy. The criteria for PBC have recently been updated in Japan.11 Yamamoto et al.12 have reported a diagnostic scoring system for PBC that includes biochemical, immunological, and pathological factors similar to those of AIH.3 Latent or early PBC exists as a specific type of PBC. Metcaff et al.13 have described early PBC as a disease entity with no apparent clinical features of PBC, showing normal results on routine liver function tests (serum alkaline phosphatase [ALP], alanine aminotransferase [ALT], and bilirubin) and AMA positivity, with histological features of PBC. This latent or early PBC is presumed to progress to typical

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PBC gradually. There is a healthy population with AMA positivity. Although these subjects are rare, they may have latent or early PBC. The differential diagnosis of typical AIH and PBC is not so difficult. However, there is no single definite diagnostic marker for these diseases. For example, ANA, especially the centromere type of ANA, is prevalent in about 50% of patients with PBC. Also, AMA is negative in 10% of PBC patients, while AMA is positive in about 20% of patients with AIH. Basically, AIH is diagnosed by the exclusion of other diseases. Popper and Shaffner14 have reported on PBC-CAH overlap syndrome. These patients are characterized by scanty cholestasis, no distinct elevation of serum ALP and cholesterol, positivity for AMA and anti-smooth muscle antibody (ASMA), and histological features of CNSDC and chronic hepatitis. Overlap syndrome has not been established as a single disease and may have diverse pathological processes. For the putative mechanism of overlap syndrome, the following possibilities may be considered.15 (1) Patients with overlap syndrome may suffer from two diseases at the same time. (2) Overlap syndrome may represent a cholestatic form of AIH or a hepatitic form of PBC. Lohse et al.16 provided evidence suggesting that overlap syndrome is a hepatitic form of PBC. The patients they described had HLA loci that were characteristic of AIH (B8, DR3, or DR4), and they were positive for anti-M2 antibody and had CNSDC in the liver, although not all of the patients had AIH-specific HLA haplotypes. (3) Overlap syndrome may represent serological and histological variants of AIH or PBC. If this is so, the overlapping features of AIH and PBC are manifested as part of a continuous spectrum of autoimmune liver disease. We analyzed Japanese patients with overlap syndrome.15 Patients with definite overlap syndrome showed immunological and histological features of both PBC and AIH, but resembled AIH in their biochemical findings. Concurrent features of AIH and PBC are considered to be epiphenomena. (4) Overlap syndrome may be an independent disease entity. At present, overlap syndrome is considered to be a variant form of AIH, and PBC, but not an independent disease entity. The mechanism underlying the pathogenesis of overlap syndrome is still completely unknown. A CAH-PBC mixed type of autoimmune liver disease was described by Berg and Binder.17 These patients were positive for AMA, had histological features of both cholestasis and aggressive hepatitis in the liver, and responded to glucocorticoid. They had clinical features characteristic of both AIH and PBC. In most patients, AIH appeared during the clinical course of PBC. However, sometimes AIH became apparent independently. These patients may benefit from therapy for AIH. This mixed type is not an independent disease

entity, but, rather, a simple combination of AIH and PBC, which is very rare. AIC was reported by Brunner and Klinge.18 These patients had cholangitis, were positive for ANA, negative for AMA by immunofluorescence, and responsive to glucocorticoid. We have reported hepatitis-like features both peritoneoscopically and histologically in patients with AIC.19 However, AMA was positive by an immunoblotting technique in AIC.20 Both good and poor responses to glucocorticoid therapy have been reported in AIC.21 At present, AIC is not considered to be a single disease entity, but is considered to be one form of PBC. The diagnosis of each autoimmune liver disease is important, because the therapy and prognosis are different. In this context, a universal diagnostic system is needed for autoimmune liver diseases. In this issue of the Journal of Gastroenterology, Zeniya and colleagues22 have reported seven variables that may be important for the diagnosis of autoimmune liver diseases.22 They performed multiple logistic regression analyses to determine variables that could distinguish AIH and PBC from non-AIH and non-PBC, respectively, in a prototype group. Seven variables—three laboratory tests (ALP, ALT, and AMA) and four histological findings (bile duct injury, bile duct loss, hepatocyte rosette formation, and lobular hepatitis)—were selected. Interestingly, the same variants were selected for AIH and, PBC. This work is worthy because it is a nationwide, large-scale study in which clinicians and pathologists joined together. It may be possible to diagnose autoimmune liver diseases using these seven variables. Zeniya and colleagues have proposed that AIC is one form of PBC, and they also showed a limited prevalence of overlap syndrome in Japan. However, there are several points in the study that deserve serious consideration. First, this study is retrospective in nature and analyses were done based on data at a single point in time in the patients. As mentioned above, the extent and nature of autoimmune liver diseases may change with time, especially in some groups of patients. This indicates the necessity for serial observations. Secondly, the seven variables are somewhat different from those proposed earlier. For AIH, ANA, IgG/g-globulin in sera, interface hepatitis, and plasma cell infiltration in liver have been excluded. On the other hand, bile duct injury and bile duct loss are included, compared with previous criteria.3,5 For PBC, cholesterol, IgM in sera, CNSDC, and granuloma in liver have been excluded, while, on the other hand, hepatocyte rosette formation is included.11,12 CNSDC is an important diagnostic marker for PBC. This can be seen in serial liver biopsy sections. Thirdly, in the system proposed by Zeniya et al.,22 there are many pathological findings compared to clinical markers, and

N. Horiike and M. Onji: New diagnostic system for autoimmune liver diseases

diagnosis according to the pathological findings may not be easy for general physicians. Zeniya et al.22 reported that most patients could be classified as having either PBC or AIH. Firstly, for the diagnosis of AIH and PBC in the in validation group, the sensitivity was 86.3% and 92.4%, respectively. However, the specificity was 82.5% and 63.7%, respectively. The specificity for PBC was slightly lower, than that for AIH, though the authors noted that the original diagnoses were not necessarily correct. Secondly, in patients with AIC, most patients were judged as having PBC. This result supports the concept that AIC is one form of PBC. Thirdly, overlap syndrome was found in 5 of 314 patients (the original diagnoses were 131 patients with AIH, 145 with PBC, and 38 with AIH-PBC overlap). Of the 38 patients originally diagnosed with overlap syndrome, only 2 were classified with this syndrome by the system of Zeniya et al.22 Talwalker et al.23 reported the absence of definite overlap syndrome in patients with PBC, though the incidence of probable overlap syndrome was 19%. On the other hand, Chazouilleres et al.24 reported that the frequency of overlap syndrome in patients with PBC was 9.2%. Czaja25 reported that overlap was detected in 19% of patients with PBC and 5% of patients with AIH.25 We have reported that there is a definite group of patients with overlap syndrome in Japan.15 Definite overlap syndrome has shown high scores on both the PBC scoring system12 and the international AIH scoring system,3 and the syndrome seemed to be distinguishable as either PBC or AIH.3 Thus, the frequency of overlap syndrome varied in different reports. This variation may be due to differences in the diagnostic criteria and in the subjects in each report. It should be remembered that, basically, there are no specific diagnostic systems for overlap syndrome. The report of Zeniya and colleagues22 can contribute to our knowledge of autoimmune liver disease in various aspects. It may be useful for the differential diagnosis of PBC and AIH. Also, their study has shown that AIC is one form of PBC and that there are few patients with overlap syndrome in Japan. In future, a large-scale prospective study, including details of clinical courses and outcomes of therapy, is needed to draw a conclusion about the numbers of patients with overlap syndrome in Japan. In addition, we expect that cooperative research with investigators in Europe and the United States will evaluate the validity of the scoring system proposed by Zeniya et al.22 Such research would also expose trends in the clinical research of autoimmune liver diseases in Japan. Recently, differential gene expression profiles in PBC have been reported.26 Further studies are needed both to clarify the pathogens involved, including target antigens, and the etiological genes, as well as to obtain precise clinical data.

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Norio Horiike M.D., and Morikazu Onji, M.D. Third Department of Internal Medicine, Ehime University School of Medicine, Shitsukawa, Toon 7910295, Japan References 1. Mackay IR, Weiden S, Hasker I. Autoimmune hepatitis. Ann NY Acad Sci 1965;124:767–80. 2. Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993;18:998–1005. 3. Alvarez F, Berg PA, Bianchi FB, Bianchi P, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–38. 4. Toda G, Zeniya M, Watanabe F, Imawari M, Kiyosawa K, Nishioka M, et al. Present status of autoimmune hepatitis in Japan; correlating the characteristics with international criteria in an area with a high rate of HCV infection. J Hepatol 1997;26:1207– 12. 5. Toda G. Diagnostic guideline of autoimmune hepatiis 1996 (in Japanese). Acta Hepatol Jpn 1996;37:298–300. 6. Nikias GA, Batts KP, Czaija AJ. The nature and prognostic implications of autoimmune hepatitis with an acute presentation. J Hepatol 1994;21:866–71. 7. Abe M, Hiasa Y, Masumoto Y, Kumagi T, Akbar SM, Ninomiya T, et al. Clinical characteristics of autoimmune hepatitis with histological features of acute hepatitis. Hepatol Res 2001;21:213– 9. 8. Karim S, Akbar SMF, Abe M, et al. A case of acute exacerbation of autoimmune hepatitis showing spontaneous remission and acute exacerbation. Allergology International 2003;52:105–9. 9. Kaneko A, Kato M, Fujimoto M, et al. Latent autoimmune hepatitis in non-B, non-C chronic liver diseases (in Japanse). Acta Hepatol Jpn 1996;37:688–95. 10. Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in children: a 20-year experience. Hepatology 1997;25:541–7. 11. Toda G, Ohnishi S. The revised diagnostic criteria of primary biliary cirrhosis (in Japanese). Acta Hepatol Jpn 2005;46:262–3. 12. Yamamoto K, Terada R, Okamoto R, Hiasa Y, Abe M, Onji M, et al. A scoring system for primary biliary cirrhosis and its application for variant forms of autoimmune liver disease. J Gastroenterol 2003;38:52–9. 13. Metcalf JV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OF. Natural history of early primary biliary cirrhosis. Lancet 1996;348:1309–402. 14. Popper H, Shaffner F. Nonsuppurative destructive chronic cholangitis and chronic hepatitis. In: Popper H, Shaffner F, editors. Progress in liver disease, vol. III. New York: Grune and Stratton; 1970. p. 336–54. 15. Onji M, Yamamoto K. Putative mechanism of overlap syndrome: what is the entity? In: Tsuji T, Higashi T, Zeniya M, et al., editors. Molecular biology and immunology in hepatology. Tokyo: Elsevier; 2002. p. 263–71. 16. Lohse AW, zum Buschenfelde KH, Franz B, Kanzler S, Gerken G, Dienes HP. Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatic form of PBC in genetically susceptible individuals Hepatology 1999;29:1078–84. 17. Berg PA, Binder T. Demonstration of mitochondrial antibodies in sera from patients with chronic liver disease reacting with two different types of complement-fixing antigens. In: Gentilini P, et al., editors. Chronic hepatitis. Basel: Karger; 1976. p. 79–85. 18. Brunner G, Klinge O. A cholangitis with antimitochondrial (immuno-cholangitis) resembling chronic non-suppurative destructive cholangitis. Dtsch Med Wochenschr 1987;112:1454–58.

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toimmune hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system. Am J Gastroenterol 2002;897:1191–7. 24. Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998;28:296–301. 25. Czaja AJ. Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 1998;28:360–5. 26. Honda M, Kawai H, Shirota Y, Yamashita T, Kaneko S. Differential gene expression profiles in stage 1 primary biliary cirrhosis. Am J Gastroenterol 2005;100:2019–30.